Neutropenia, Severe Congenital, 4, Autosomal Recessive

A number sign (#) is used with this entry because severe congenital neutropenia-4 (SCN4) and Dursun syndrome are both caused by homozygous mutation in the G6PC3 gene (611045) on chromosome 17q21.

For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).

Clinical Features

Boztug et al. (2009) reported an extended consanguineous kindred from Aramean, Turkey, in which 4 children had a syndrome comprising severe congenital neutropenia, cardiac abnormalities, and a prominent superficial venous pattern. Three presented with neonatal sepsis, the fourth with pneumonia and sepsis, consistent with increased susceptibility to bacterial infections. Cardiac defects included atrial septal defect, cor triatriatum, and mitral insufficiency. Three patients also had hepatosplenomegaly, and 2 had intermittent thrombocytopenia. Eight additional unrelated patients were later ascertained, all showing similar features. Four of 6 males had cryptorchidism, and 1 child each had urachal fistula, microcephaly, inner-ear hearing loss, and cleft palate.

Arostegui et al. (2009) reported a 22-year-old Moroccan man with SCN4 who presented at age 11 years. He had recurrent bacterial infections since childhood, resulting in bronchiectasis and loss of teeth. He showed poor overall growth and educational delay, and laboratory studies showed decreased absolute neutrophil count and anemia. Bone marrow biopsy showed a paucity of granulocytes beyond the promyelocyte stage. Other features included cryptorchidism, atrial septal defect, and prominent subcutaneous venous circulation. There was no family history of a similar disorder. He showed good response to iron supplementation and recombinant G-CSF. During follow-up, he had intermittent and unexplained thrombocytopenia. Genetic analysis identified a homozygous truncating mutation in the G6PC3 gene.

McDermott et al. (2010) reported 2 sibs with SCN4 and recurrent infections beginning in infancy. Both had multiple additional clinical abnormalities, including microcephaly, prominent superficial veins, mild sensorineural hearing loss, poor growth, iron deficiency anemia, giant platelets, muscle weakness, and joint laxity. The sister had an atrial septal defect, and the brother had mitral valve abnormalities, cryptorchidism, and asthma. Treatment with G-CSF resulted in clinical improvement, and both were in the appropriate school levels at ages 13 and 9 years, respectively.

Banka et al. (2011) reported a large consanguineous kindred of Arab-Muslim descent in which 4 individuals had SCN4 confirmed by genetic analysis (611045.0001). Three of the patients, 2 females and 1 male, were 25 years of age or older, allowing for delineation of the phenotype in adults. All adults had recurrent infections due to neutropenia and characteristic superficial venous pattern with varicose veins, resulting in a venous stasis ulcer in 1 patient. These 3 patients also had mild learning disability, which was also present in another family member without SCN4. Other features included poor growth and failure to thrive in infancy and poor development of secondary sexual characteristics. The male patient had unilateral renal agenesis and hydronephrosis, and a female patient had patent ductus arteriosus and atrial septal defect. She died of sepsis at age 25. One female had mild kyphosis, tapering fingers, and clinodactyly of the fourth and fifth fingers, and the male had broad thumbs. Laboratory studies showed low white blood cell count and anemia in all, increased serum TSH in 2, and decreased HDL with increased amylase in 1. The fourth patient, a 2-year-old boy, had pulmonary valve stenosis, patent ductus arteriosus, atrial septal defect, and primary pulmonary hypertension. He had increased gamma-glutamyltransferase and calcifications of the liver at age 7 days, and later developed choledocholithiasis. He showed failure to thrive and developmental delay. Mild dysmorphic features included plagiocephaly, sparse scalp hair, midface hypoplasia, tented mouth, pectus carinatum, and loose skin on the palms and soles. Banka et al. (2011) concluded that the phenotype of SCN4 may include additional features, and that patients should be monitored for poor growth, endocrine dysfunction, dyslipidemia, and liver and kidney function.

Dursun Syndrome

Dursun et al. (2009) described a Turkish brother and sister, born of nonconsanguineous parents, with pulmonary arterial hypertension, cardiac abnormalities including secundum-type atrial septal defect, hematologic abnormalities including intermittent neutropenia, lymphopenia, monocytosis, and anemia, and marked thymic involution. Both sibs also had pectus carinatum, long fingers, proximally placed thumb, broad nasal bridge, and high-arched palate. The male proband had bilateral inguinal hernias and undescended testes. In a follow-up of the patients reported by Dursun et al. (2009), Banka et al. (2010) noted that both children died of severe respiratory distress due to primary pulmonary hypertension at age 18 months. Banka et al. (2010) stated that the report of these children expanded the phenotype of SCN4, indicating that monocytosis, lymphopenia, and hypoplasia of the erythroid cell line resulting in anemia may also be features of the disorder.

Mapping

By linkage analysis of 2 consanguineous Turkish families with syndromic congenital neutropenia, Boztug et al. (2009) found linkage to a region on chromosome 17q21 (maximum 2-pedigree multipoint lod score of 5.74 at markers D17S932, D17S950, and D17S806).

Molecular Genetics

In affected members of a large consanguineous Turkish family and an unrelated Turkish child with SCN4, Boztug et al. (2009) identified a homozygous mutation in the G6PC3 gene (611045.0001). In vitro functional expression assays showed that patient neutrophils carrying the mutation had increased susceptibility to apoptosis, although the oxidative burst was normal. Eight additional mutations (see, e.g., 611045.0002-611045.0005, 611045.0007) were identified in 7 other patients with the disorder.

In 2 sibs with SCN4 and multiple clinical abnormalities, McDermott et al. (2010) identified a homozygous mutation in the G6PC3 gene (611045.0007).

Dursun Syndrome

In 1 of the Turkish children with Dursun syndrome (Dursun et al., 2009), Banka et al. (2010) identified a homozygous mutation in the G6PC3 gene (M116V; 611045.0006). Each unaffected parent was heterozygous for the mutation, which was not found in 176 control chromosomes. The findings suggested that Dursun syndrome can be considered a subset of SCN4. Banka et al. (2010) noted that dysfunction of G6PC3 can result in defects in glucose metabolism, which may be associated with primary pulmonary hypertension.

Pathogenesis

In bone marrow biopsies of 2 sibs with SCN4 due to homozygous G260R (611045.0007) mutation, McDermott et al. (2010) found the presence of mature neutrophils despite markedly decreased neutrophils in the peripheral blood. The bone marrow also showed a predominance of atypical mononuclear megakaryocytes, myeloid hyperplasia, and vacuolization of the myeloid precursors. These features were consistent with myelokathexis and cytokine activation. Peripheral blood neutrophils and NK cells had increased expression of CXCR4 (162643), and G-CSF treatment resulted in a dose-dependent decrease of CXCR4. McDermott et al. (2010) concluded that the neutropenia in their patients resulted from a combination of decreased release of mature neutrophils from the bone marrow, increased apoptosis of peripheral blood neutrophils, and decreased superoxide production.